Increased vulnerability to ischemia/reperfusion-induced ventricular tachyarrhythmias by pre-ischemic inhibition of nitric oxide synthase in isolated rat hearts

• Published in: Cardiovascular pathology Vol. 12; no. 1; pp. 49 - 56
• Main Authors: Kawahara, Koichi, Takase, Marei, Yamauchi, Yoshiko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2003
• Subjects: Animals; Arginine - pharmacology; Diazoxide - pharmacology; Enzyme Inhibitors - pharmacology; Heart - drug effects; Hypoxanthines - pharmacology; Ischemia; K-channel; Male; Mitochondria, Heart - metabolism; Myocardium - enzymology; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Donors - pharmacology; Nitric Oxide Synthase - antagonists & inhibitors; Organ Culture Techniques; Potassium Channels - drug effects; Potassium Channels - metabolism; Rats; Rats, Wistar; Reperfusion; Reperfusion Injury - complications; Reperfusion Injury - enzymology; S-Nitroso-N-Acetylpenicillamine - pharmacology; Tachycardia, Ventricular - etiology; Vasodilator Agents - pharmacology; Ventricular arrhythmias; Ventricular arrhythmias; Reperfusion; Ischemia; K-channel; Nitric oxide
• ISSN: 1054-8807; 1879-1336
• DOI: 10.1016/S1054-8807(02)00155-2

Introduction: The relationship between vulnerability to reperfusion-induced ventricular tachyarrhythmias, such as ventricular tachycardia (VT) and fibrillation (VF), and the endogenous activity of nitric oxide synthase (NOS) has not been well documented. The objective of the present study was to clarify whether the vulnerability to reperfusion-induced VT/VF changes with preishemic, sustained inhibition of NOS. Methods: The experiments were performed using Langendorff-perfused isolated rat hearts, in which left ventricular pressure (LVP) and left ventricular cardiomyograms (LVCMGs) were measured. Results: A pre-ischemic, sustained inhibition of NOS resulted in an increased vulnerability to reperfusion-induced VT/VF, and the increase was markedly attenuated by co-treatment with l-arginine or by post-ischemic treatment with 2,4-diamino-6-hydroxypyrimidine (DAHP), an inhibitor of tetrahydrobiopterin (BH 4) synthesis. We then tried to elucidate whether nitric oxide (NO) and superoxide were produced during reperfusion, and ATP-sensitive potassium channels (K ATP), especially mitochondrial ATP-sensitive potassium channels (mitoK ATP), are involved in the increased vulnerability. Post-ischemic inhibition of NOS and treatment with a NO scavenger attenuated the increased vulnerability to reperfusion-induced VT/VF, but post-ischemic treatment with a superoxide scavenger did not. In addition, post-ischemic treatment with S-nitroso- N-acetyl- dl-penicillamine (SNAP), a NO donor, or with diazoxide, a selective opener of mitoK ATP, increased the VT/VF duration during reperfusion. The increased vulnerability to VT/VF was attenuated by the treatment with a selective mitoK ATP blocker. Conclusion: The results suggest that a pre-ischemic, sustained inhibition of NOS increases the vulnerability to reperfusion-induced VT/VF, and the NO-mitoK ATP pathway is one of the possible factors contributing to the increased vulnerability to VT/VF.